Liehr, Molecular Pharmacology, 23, 278 (1983) discloses the fact that, as contrasted with 17.beta.-estradiol, 2-fluoro-17.beta.-estradiol did not induce renal clear-cell carcinoma in male Syrian hamsters at equipotent estrogenic doses.
Thus, there is a renewed interest in 2-fluoro-17.beta.-estradiol which compound was first described by Utne et al. J. Org. Chem., 33, 2469 (1968). The Utne procedure involved nitration of estrone in the 2-position and the 4-position, separation of the two isomers, conversion of the 3-phenolic hydroxyl of the 2-nitro estrone to an ether, reduction of the nitro group to an amine, diazotization of the amine including preparation of the fluoroborate salt, decomposition of the salt to yield 2-fluoroestrone 3-methyl ether, reduction of the 17-ketone group with sodium borohydride and demethylation of the ether to regenerate the phenol. This procedure involves many steps, the initial nitration produces a mixture of isomers, and the yields are not as high as would be desirable in a commercial process.
Neeman et al. J. Chem. Soc. (Perkin Transactions 1), 1972, 2300 used a different approach to the preparation of 2-fluoro-17.beta.-estradiol. This approach involved employing, as a starting material, 10.beta.-hydroxyestr-4-ene-3,17-dione. This compound was epoxidized to yield the 4.beta.,-5.beta.-epoxy derivative and the epoxy compound fluorinated with gaseous hydrogen fluoride in chloroform-ethanol to yield, ultimately, a 2-fluoro-10.beta.-hydroxyestr-4-ene-3,17-dione. Dehydration of this compound with thionyl chloride produced 2-fluoroestrone, reduction of which with sodium borohydride yielded 2-fluoro-3,17.beta.-estradiol.
The ultimate starting material for the Neeman synthesis, 19-nortestosterone, is not readily obtainable. The authors also refer to their prior specific synthesis of 4-fluoro-17.beta.-estradiol, a compound also prepared by Palmer et al. J. Labelled Cmpds., 16, 14-16 (1979) and by Eakins et al.--see International Journal of Applied Radiation and Isotopes, 30, 695 (1979). These latter authors also prepared 4-fluoroestrone, 2,4-diiodoestradiol and 2-iodoestradiol. 2-Iodo-17.beta.-estradiol was prepared from 17.beta.-estradiol and sodium iodide. The preparation involved evaporation of any solvent and melting the two solid materials together at 180.degree. C. Since radioactive iodine had been used, autoradiography could be used to distinguish the desired 2-iodo-17.beta.-estradiol from all other substances in the mixture; thus separation by chromatography was possible. These radioactively labelled compounds, I.sup.125 -2-iodoestradiol and F.sup.18 -4-fluoroestradiol, were designed for use in scanning for estrogen dependent tumors or for scanning the prostate.
Heiman et al., J. Med. Chem., 23, 994 (1980) sought superior methods of preparing halogenated estrogens for use as estrogen receptor-based imaging agents. The authors prepared 3-fluorohexestrol by procedures similar to those employed by Utne et al. (loc. cit.) for preparing 2-fluoro-17.beta.-estradiol.
An adjacent paper by the same group of authors, Goswami et al., J. Med. Chem., 23, 1002 (1980), discusses the preparation of side-chain halogenated hexestrol derivatives.
A third paper from the same group, Ng et al., J. Org. Chem., 46, 2520 (1981), describes the fluorination of hexestrol (a phenolic estrogen), ortho to the phenol group, during which process an amine group is converted to an arylazide and the azide decomposed in the presence of HF. In this last step, fluorine replaces the azide grouping.
Santaniello et al., J.C.S. Chem. Comm., 1981, 217, 1157 (1981) attempted to prepare orthohalogen derivatives of estradiol or of the corresponding ethers or acyl compounds. The authors regioselectively chloromercurated the C.sub.2 -position of 3-methoxy-17.beta.-acetoxyestra-1,3,5-triene. This chloromercury derivative was readily converted to a 2-bromo and a 2-iodo derivative with Br.sub.2 or I.sub.2 respectively. An expansion of the original paper can be found in J.C.S. Chem. Comm., 1157, (1982).
Njar et al., J. Org. Chem., 48, 1007 (1983) describe the synthesis of 4-fluoro-17.beta.-estradiol, 4-fluoroestrone and similar compounds. 4-Fluoro-17.beta.-estradiol was prepared from 4-fluoro-19-nortestosterone by dehydrogenation with selenium dioxide.
Adam et al., Can. J. Chem., 61, 658 (1983) describe the preparation of fluorobenzene from phenyl mercury trifluoroacetate and elemental fluorine.
The reagent, acetyl hypofluorite, has been described by Rozen et al., J.C.S. Chem. Comm., 443 (1981) who describe this compound as a new electrophilic fluorinating agent.
Shiue et al., J. Nucl. Med., 23, 899 (1982) used .sup.18 F-labeled acetyl hypofluorite to fluorinate 2-deoxy-D-glucose. Yields were about 20%.
Mantescu et al., Radiopharm. and Label Cmpds., 395 (1973) employed a mixture of glacial acetic acid and K.sup.18 F as a fluorinating agent to prepare certain steroid hormones containing radioactive fluorine. These hormones included 4-fluorotestosterone and 2,4-difluoroestrone. The authors adopted the procedure of iodinating estrone at the 2 and 4 carbons and then replacing the iodine with radiofluorine using the KF-acetic anhydride procedure.
It is apparent that no commercially feasible synthetic route is available for preparing 2-fluoro-17.beta.-estradiol; i.e., a route based on readily available and inexpensive starting materials, employing a minimal number of steps and capable of giving good yields of all products. It is an object of the invention to provide such a procedure.